Compounds and uses thereof

ABSTRACT

N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide, N-[3-(4-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide, and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof are active on at least one Raf protein kinase. Also described are methods of use thereof to treat diseases and conditions, including diseases and conditions associated with activity of Raf protein kinases, including pain and polycystic kidney disease.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. provisional application Ser.Nos. 61/159,401 and 61/159,407 filed Mar. 11, 2009, each of which isincorporated herein in its entirety.

FIELD OF THE INVENTION

Disclosed are novel compounds and uses thereof. In certain embodimentsdisclosed compounds are kinase inhibitors.

SUMMARY OF THE INVENTION

In certain aspects and embodiments disclosed herein, compounds areprovided, as well as various salts thereof, formulations thereof,conjugates thereof, derivatives thereof, forms thereof and uses thereof.Also contemplated in accordance with the present invention are methodsfor the use of compounds in treating diseases and conditions associatedwith regulation of the activity of one or more Raf kinases, includingany mutations of one or more Raf kinases. Thus, in certain embodimentsuses are provided for compounds and salt forms thereof in therapeuticmethods involving modulation of Raf protein kinases. In one embodiment,compounds or pharmaceutically acceptable salts thereof, are used fortherapeutic methods involving modulation of Raf protein kinases,including treatment of a variety of indications, including, but notlimited to, pain and polycystic kidney disease.

In a first aspect, a compound selected from the group consisting ofN-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide(P-0001),N-[3-(4-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide(P-0002), any salt thereof, any formulation thereof, any conjugatethereof, any derivative thereof, and any form thereof is provided. Incertain embodiments P-0001, P-0002, or a salt thereof, formulationthereof, conjugate thereof, derivative thereof, or form thereof is aninhibitor of one or more Raf protein kinases, including A-Raf, B-Raf,and c-Raf-1 (including any mutations of these kinases).

In a second aspect the compoundN-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide(P-0001), or a salt thereof, formulation thereof, conjugate thereof,derivative thereof, or form thereof is provided. In certain embodimentsP-0001, or a salt thereof, formulation thereof, conjugate thereof,derivative thereof, or form thereof is an inhibitor of one or more Rafprotein kinases, including A-Raf, B-Raf, and c-Raf-1 (including anymutations of these kinases).

In a third aspect the compoundN-[3-(4-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide(P-0002), or a salt thereof, formulation thereof, conjugate thereof,derivative thereof, or form thereof is provided. In certain embodimentsP-0002, or a salt thereof, formulation thereof, conjugate thereof,derivative thereof, or form thereof is an inhibitor of one or more Rafprotein kinases, including A-Raf, B-Raf, and c-Raf-1 (including anymutations of these kinases).

In reference to compounds P-0001 and P-0002, unless clearly indicated tothe contrary, specification of the compound includes salts of suchcompound (including pharmaceutically acceptable salts), formulations ofsuch compound (including pharmaceutically acceptable formulations),conjugates thereof, derivatives thereof, forms thereof, and prodrugsthereof.

In a fourth aspect, the invention provides methods for treating a Rafprotein kinase mediated disease or condition in an animal subject,wherein the method involves administering to the subject an effectiveamount of either or both of P-0001 or P-0002. In one embodiment, themethod involves administering to the subject an effective amount ofeither or both of P-0001 or P-0002 in combination with one or more othertherapies for the disease or condition. In one embodiment, the diseaseis pain. In one embodiment, the disease is polycystic kidney disease.

In a fifth aspect, compositions are provided that include atherapeutically effective amount of either or both of P-0001 or P-0002and at least one pharmaceutically acceptable carrier, excipient, and/ordiluent. In certain embodiments, the composition can include either orboth of P-0001 or P-0002, along with one or more compounds that aretherapeutically effective for the same disease indication. In relatedembodiments, the composition includes either or both of P-0001 orP-0002, along with one or more compounds that are therapeuticallyeffective for the same disease indication, wherein the compounds have asynergistic effect on the disease indication. In one embodiment, thedisease is pain. In one embodiment, the disease is polycystic kidneydisease.

In a sixth aspect, the invention provides methods for treating a diseaseor condition mediated by A-Raf, B-Raf, c-Raf-1, or any mutation thereofby administering to the subject an effective amount of a compositionincluding either or both of P-0001 or P-0002. In various embodiments,the invention provides methods for treating a disease or conditionmediated by A-Raf, B-Raf, c-Raf-1, or any mutation thereof byadministering to the subject an effective amount of a compositionincluding either or both of P-0001 or P-0002 in combination with one ormore other suitable therapies for treating the disease. In oneembodiment, the disease is pain. In one embodiment, the disease ispolycystic kidney disease.

In a seventh aspect, the invention provides kits that include either orboth of P-0001 or P-0002, or a composition thereof as described herein.In some embodiments, the compound or composition is packaged, e.g., in avial, bottle, flask, which may be further packaged, e.g., within a box,envelope, or bag; the compound or composition is approved by the U.S.Food and Drug Administration or similar regulatory agency foradministration to a mammal, e.g., a human; the compound or compositionis approved for administration to a mammal, e.g., a human, for a proteinkinase mediated disease or condition; the invention kit includes writteninstructions for use and/or other indication that the compound orcomposition is suitable or approved for administration to a mammal,e.g., a human, for a protein kinase-mediated disease or condition; andthe compound or composition is packaged in unit dose or single doseform, e.g., single dose pills, capsules, or the like.

In aspects and embodiments involving treatment of a disease or conditionwith either or both of P-0001 or P-0002, the invention provides methodsfor treating an A-Raf-mediated, B-Raf-mediated and/or c-Raf-1-mediateddisease or condition in an animal subject (e.g. a mammal such as ahuman, other primates, sports animals, animals of commercial interestsuch as cattle, farm animals such as horses, or pets such as dogs andcats), e.g., a disease or condition characterized by abnormal A-Raf,B-Raf, and/or c-Raf-1 activity (e.g. kinase activity). In someembodiments, invention methods may involve administering to the subjectsuffering from or at risk of an A-Raf-mediated, B-Raf-mediated and/orc-Raf-1-mediated disease or condition an effective amount of either orboth of P-0001 or P-0002. In one embodiment, the A-Raf-mediated,B-Raf-mediated, and/or c-Raf-1-mediated disease is selected from thegroup consisting of neurologic diseases, including, but not limited to,multi-infarct dementia, head injury, spinal cord injury, Alzheimer'sdisease (AD), Parkinson's disease, seizures and epilepsy; neoplasticdiseases including, but not limited to, melanoma, glioma, glioblastomamultiforme, pilocytic astrocytoma, sarcoma, carcinoma (e.g.gastrointestinal, liver, biliary tract (e.g. bile duct,cholangiocarcinoma), colorectal, lung, gallbladder, breast, pancreatic,thyroid, renal, ovarian, adrenocortical, prostate), lymphoma (e.g.histiocytic lymphoma) neurofibromatosis, gastrointestinal stromaltumors, acute myeloid leukemia, myelodysplastic syndrome, leukemia,tumor angiogenesis, neuroendocrine tumors such as medullary thyroidcancer, carcinoid, small cell lung cancer, Kaposi's sarcoma, andpheochromocytoma; pain of neuropathic or inflammatory origin, including,but not limited to, acute pain, chronic pain, cancer-related pain, andmigraine; cardiovascular diseases including, but not limited to, heartfailure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g.thrombotic microangiopathy syndromes), atherosclerosis, and reperfusioninjury; inflammation and/or proliferation including, but not limited to,psoriasis, eczema, arthritis and autoimmune diseases and conditions,osteoarthritis, endometriosis, scarring, vascular restenosis, fibroticdisorders, rheumatoid arthritis, inflammatory bowel disease (IBD);immunodeficiency diseases, including, but not limited to, organtransplant rejection, graft versus host disease, and Kaposi's sarcomaassociated with HIV; renal cystic, or prostatic diseases, including, butnot limited to, diabetic nephropathy, polycystic kidney disease,nephrosclerosis, glomerulonephritis, prostate hyperplasia, polycysticliver disease, tuberous sclerosis, Von Hippel Lindau disease, medullarycystic kidney disease, nephronophthisis, and cystic fibrosis; metabolicdisorders, including, but not limited to, obesity; infection, including,but not limited to Helicobacter pylori, Hepatitis and Influenza viruses,fever, HIV, and sepsis; pulmonary diseases including, but not limitedto, chronic obstructive pulmonary disease (COPD) and acute respiratorydistress syndrome (ARDS); genetic developmental diseases, including, butnot limited to, Noonan's syndrome, Costello syndrome,(faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faciocutaneoussyndrome (CFC), and neural crest syndrome abnormalities causingcardiovascular, skeletal, intestinal, skin, hair and endocrine diseases;and diseases associated with muscle regeneration or degeneration,including, but not limited to, sarcopenia, muscular dystrophies(including, but not limited to, Duchenne, Becker, Emery-Dreifuss,Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal andCongenital Muscular Dystrophies), motor neuron diseases (including, butnot limited to, amyotrophic lateral sclerosis, infantile progressivespinal muscular atrophy, intermediate spinal muscular atrophy, juvenilespinal muscular atrophy, spinal bulbar muscular atrophy, and adultspinal muscular atrophy), inflammatory myopathies (including, but notlimited to, dermatomyositis, polymyositis, and inclusion body myositis),diseases of the neuromuscular junction (including, but not limited to,myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenicsyndrome), myopathies due to endocrine abnormalities (including, but notlimited to, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency). In one embodiment, the diseaseor condition is pain or polycystic kidney disease.

In an eighth aspect, either or both of P-0001 or P-0002, can be used inthe preparation of a medicament for the treatment of an A-Raf-mediated,B-Raf-mediated or c-Raf-1-mediated disease or condition selected fromthe group consisting of neurologic diseases, including, but not limitedto, multi-infarct dementia, head injury, spinal cord injury, Alzheimer'sdisease (AD), Parkinson's disease, seizures and epilepsy; neoplasticdiseases including, but not limited to, melanoma, glioma, glioblastomamultiforme, pilocytic astrocytoma, sarcoma, carcinoma (e.g.gastrointestinal, liver, biliary tract (e.g. bile duct,cholangiocarcinoma), colorectal, lung, gallbladder, breast, pancreatic,thyroid, renal, ovarian, adrenocortical, prostate), lymphoma (e.g.histiocytic lymphoma) neurofibromatosis, gastrointestinal stromaltumors, acute myeloid leukemia, myelodysplastic syndrome, leukemia,tumor angiogenesis, neuroendocrine tumors such as medullary thyroidcancer, carcinoid, small cell lung cancer, Kaposi's sarcoma, andpheochromocytoma; pain of neuropathic or inflammatory origin, including,but not limited to, acute pain, chronic pain, cancer-related pain, andmigraine; cardiovascular diseases including, but not limited to, heartfailure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g.thrombotic microangiopathy syndromes), atherosclerosis, and reperfusioninjury; inflammation and/or proliferation including, but not limited to,psoriasis, eczema, arthritis and autoimmune diseases and conditions,osteoarthritis, endometriosis, scarring, vascular restenosis, fibroticdisorders, rheumatoid arthritis, inflammatory bowel disease (IBD);immunodeficiency diseases, including, but not limited to, organtransplant rejection, graft versus host disease, and Kaposi's sarcomaassociated with HIV; renal cystic, or prostatic diseases, including, butnot limited to, diabetic nephropathy, polycystic kidney disease,nephrosclerosis, glomerulonephritis, prostate hyperplasia, polycysticliver disease, tuberous sclerosis, Von Hippel Lindau disease, medullarycystic kidney disease, nephronophthisis, and cystic fibrosis; metabolicdisorders, including, but not limited to, obesity; infection, including,but not limited to Helicobacter pylori, Hepatitis and Influenza viruses,fever, HIV, and sepsis; pulmonary diseases including, but not limitedto, chronic obstructive pulmonary disease (COPD) and acute respiratorydistress syndrome (ARDS); genetic developmental diseases, including, butnot limited to, Noonan's syndrome, Costello syndrome,(faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faciocutaneoussyndrome (CFC), and neural crest syndrome abnormalities causingcardiovascular, skeletal, intestinal, skin, hair and endocrine diseases;and diseases associated with muscle regeneration or degeneration,including, but not limited to, sarcopenia, muscular dystrophies(including, but not limited to, Duchenne, Becker, Emery-Dreifuss,Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal andCongenital Muscular Dystrophies), motor neuron diseases (including, butnot limited to, amyotrophic lateral sclerosis, infantile progressivespinal muscular atrophy, intermediate spinal muscular atrophy, juvenilespinal muscular atrophy, spinal bulbar muscular atrophy, and adultspinal muscular atrophy), inflammatory myopathies (including, but notlimited to, dermatomyositis, polymyositis, and inclusion body myositis),diseases of the neuromuscular junction (including, but not limited to,myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenicsyndrome), myopathies due to endocrine abnormalities (including, but notlimited to, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency). In one embodiment, the diseaseor condition is pain or polycystic kidney disease.

Either or both of P-0001 and P-0002, as provided herein, demonstratedesirable inhibitory activity on Raf kinases, with selectivity relativeto other kinases, and further demonstrate one or more desirableproperties, such as greater solubility, lesser Cyp inhibition, and thelike.

Additional aspects and embodiments will be apparent from the followingDetailed Description and from the claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein the following definitions apply unless clearly indicatedotherwise:

All atoms within P-0001 or P-0002 described herein are intended toinclude any isotope thereof, unless clearly indicated to the contrary.It is understood that for any given atom, the isotopes may be presentessentially in ratios according to their natural occurrence, or one ormore particular atoms may be enhanced with respect to one or moreisotopes using synthetic methods known to one skilled in the art. Thus,hydrogen includes for example ¹H, ²H, ³H; carbon includes for example¹¹C, ¹²C, ¹³C, ¹⁴C; oxygen includes for example ¹⁶O, ¹⁷O, ¹⁸O; nitrogenincludes for example ¹¹C, ¹⁵N; sulfur includes for example ³²S, ³³S,³⁴S, ³⁵S, ³⁶S, ³⁷S, ³⁸S; fluoro includes for example ¹⁷F, ¹⁸F, ¹⁹F;chloro includes for example ³⁵Cl, ³⁶Cl, ³⁷Cl, ³⁸Cl, ³⁹Cl; and the like.

As used herein, the terms “treat”, “treating”, “therapy”, “therapies”,and like terms refer to the administration of material, e.g., any one ormore compound(s) as described herein in an amount effective to prevent,alleviate, or ameliorate one or more symptoms of a disease or condition,i.e., indication, and/or to prolong the survival of the subject beingtreated.

As used herein, the term “Raf protein kinase mediated disease orcondition” refers to a disease or condition in which the biologicalfunction of a Raf protein kinase (also referred to as Raf kinase, orRaf), including any of A-Raf protein kinase, B-Raf protein kinase orc-Raf-1 protein kinase, or any mutation thereof, affects thedevelopment, course, and/or symptoms of the disease or condition, and/orin which modulation of Raf alters the development, course, and/orsymptoms of the disease or condition. The Raf mediated disease orcondition includes a disease or condition for which Raf modulationprovides a therapeutic benefit, e.g. wherein treatment with Rafinhibitor(s), including one or more compound(s) described herein,provides a therapeutic benefit to the subject suffering from or at riskof the disease or condition.

As used herein, the term “A-Raf protein kinase mediated disease orcondition,” and the like refer to a disease or condition in which thebiological function of an A-Raf protein kinase (also referred to asA-Raf kinase, or A-Raf), including any mutations thereof, affects thedevelopment, course, and/or symptoms of the disease or condition, and/orin which modulation of A-Raf alters the development, course, and/orsymptoms of the disease or condition. The A-Raf mediated disease orcondition includes a disease or condition for which A-Raf inhibitionprovides a therapeutic benefit, e.g. wherein treatment with a compoundthat inhibits A-Raf, including one or more compound(s) described herein,provides a therapeutic benefit to the subject suffering from or at riskof the disease or condition.

As used herein, the term “B-Raf protein kinase mediated disease orcondition,” and the like refer to a disease or condition in which thebiological function of a B-Raf protein kinase (also referred to as B-Rafkinase, or B-Raf), including any mutations thereof, such as B-Raf V600Emutant, or B-Raf V600E/T529I mutant, affects the development, course,and/or symptoms of the disease or condition, and/or in which modulationof B-Raf alters the development, course, and/or symptoms of the diseaseor condition. The B-Raf mediated disease or condition includes a diseaseor condition for which B-Raf inhibition provides a therapeutic benefit,e.g. wherein treatment with a compound that inhibits B-Raf, includingone or more compound(s) described herein, provides a therapeutic benefitto the subject suffering from or at risk of the disease or condition.

As used herein, the term “B-Raf V600E mutant protein kinase mediateddisease or condition,” and the like refer to a disease or condition inwhich the biological function of B-Raf V600E mutant protein kinase (alsoreferred to as B-Raf V600E kinase, or B-Raf V600E) affects thedevelopment, course, and/or symptoms of the disease or condition, and/orin which modulation of B-Raf V600E alters the development, course,and/or symptoms of the disease or condition. The B-Raf V600E mediateddisease or condition includes a disease or condition for which B-RafV600E inhibition provides a therapeutic benefit, e.g. wherein treatmentwith a compound that inhibits B-Raf V600E, including one or morecompound(s) described herein, provides a therapeutic benefit to thesubject suffering from or at risk of the disease or condition.

As used herein, the term “B-Raf V600E/T529I mutant protein kinasemediated disease or condition,” and the like refer to a disease orcondition in which the biological function of B-Raf V600E/T529I mutantprotein kinase (also referred to as B-Raf V600E/T529I kinase, or B-RafV600E/T5291) affects the development, course, and/or symptoms of thedisease or condition, and/or in which modulation of B-Raf V600E/T529Ialters the development, course, and/or symptoms of the disease orcondition. The B-Raf V600E/T529I mediated disease or condition includesa disease or condition for which B-Raf V600E/T529I inhibition provides atherapeutic benefit, e.g. wherein treatment with a compound thatinhibits B-Raf V600E/T529I, including one or more compound(s) describedherein, provides a therapeutic benefit to the subject suffering from orat risk of the disease or condition.

As used herein, the term “c-Raf-1 protein kinase mediated disease orcondition,” and the like refer to a disease or condition in which thebiological function of a c-Raf-1 protein kinase (also referred to asc-Raf-1 kinase, or c-Raf-1), including any mutations thereof, affectsthe development, course, and/or symptoms of the disease or condition,and/or in which modulation of c-Raf-1 alters the development, course,and/or symptoms of the disease or condition. The c-Raf-1 mediateddisease or condition includes a disease or condition for which c-Raf-1inhibition provides a therapeutic benefit, e.g. wherein treatment with acompound that inhibits c-Raf-1, including one or more compound(s)described herein, provides a therapeutic benefit to the subjectsuffering from or at risk of the disease or condition.

As used herein, the term “Raf inhibitor” refers to a compound thatinhibits at least one of A-Raf, B-Raf, c-Raf-1, or any mutationsthereof, i.e. a compound having an IC₅₀ of less than 500 nM, less than100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5nM, or less than 1 nM as determined in a generally accepted Raf kinaseactivity assay. Such compounds are preferably, but not necessarily,selective with respect to other protein kinases, i.e. when compared toanother protein kinase, the IC₅₀ for the other kinase divided by theIC₅₀ for the Raf kinase is >10, also >20, also >30, also >40, also >50,also >60, also >70, also >80, also >90, also >100. Preferably, thecompounds are selective relative to other protein kinases including, butnot limited to, CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR.

As used herein, the term “solid form” refers to a solid preparation(i.e. a preparation that is neither gas nor liquid) of apharmaceutically active compound that is suitable for administration toan intended animal subject for therapeutic purposes. The solid formincludes any complex, such as a salt, co-crystal or an amorphouscomplex, as well as any polymorph of the compound. The solid form may besubstantially crystalline, semi-crystalline or substantially amorphous.The solid form may be administered directly or used in the preparationof a suitable composition having improved pharmaceutical properties. Forexample, the solid form may be used in a formulation comprising at leastone pharmaceutically acceptable carrier or excipient.

As used herein, the term “substantially crystalline” material embracesmaterial which has greater than about 90% crystallinity; and“crystalline” material embraces material which has greater than about98% crystallinity.

As used herein, the term “substantially amorphous” material embracesmaterial which has no more than about 10% crystallinity; and “amorphous”material embraces material which has no more than about 2%crystallinity.

As used herein, the term “semi-crystalline” material embraces materialwhich is greater than 10% crystallinity, but no greater than 90%crystallinity; preferably “semi-crystalline” material embraces materialwhich is greater than 20% crystallinity, but no greater than 80%crystallinity. In one aspect of the present invention, a mixture ofsolid forms of a compound may be prepared, for example, a mixture ofamorphous and crystalline solid forms, e.g. to provide a“semi-crystalline” solid form. Such a “semi-crystalline” solid form maybe prepared by methods known in the art, for example by mixing anamorphous solid form with a crystalline solid form in the desired ratio.In some instances, a compound mixed with acid or base forms an amorphouscomplex; a semi-crystalline solid can be prepared employing an amount ofcompound component in excess of the stoichiometry of the compound andacid or base in the amorphous complex, thereby resulting in an amount ofthe amorphous complex that is based on the stoichiometry thereof, withexcess compound in a crystalline form. The amount of excess compoundused in the preparation of the complex can be adjusted to provide thedesired ratio of amorphous complex to crystalline compound in theresulting mixture of solid forms. For example, where the amorphouscomplex of acid or base and compound has a 1:1 stoichiometry, preparingsaid complex with a 2:1 mole ratio of compound to acid or base willresult in a solid form of 50% amorphous complex and 50% crystallinecompound. Such a mixture of solid forms may be beneficial as a drugproduct, for example, by providing an amorphous component havingimproved biopharmaceutical properties along with the crystallinecomponent. The amorphous component would be more readily bioavailablewhile the crystalline component would have a delayed bioavailability.Such a mixture may provide both rapid and extended exposure to theactive compound.

As used herein, the term “complex” refers to a combination of apharmaceutically active compound and an additional molecular speciesthat forms or produces a new chemical species in a solid form. In someinstances, the complex may be a salt, i.e. where the additionalmolecular species provides an acid/base counter ion to an acid/basegroup of the compound resulting in an acid:base interaction that forms atypical salt. While such salt forms are typically substantiallycrystalline, they can also be partially crystalline, substantiallyamorphous, or amorphous forms. In some instances, the additionalmolecular species, in combination with the pharmaceutically activecompound, forms a non-salt co-crystal, i.e. the compound and molecularspecies do not interact by way of a typical acid:base interaction, butstill form a substantially crystalline structure. Co-crystals may alsobe formed from a salt of the compound and an additional molecularspecies. In some instances, the complex is a substantially amorphouscomplex, which may contain salt-like acid:base interactions that do notform typical salt crystals, but instead form a substantially amorphoussolid, i.e. a solid whose X-ray powder diffraction pattern exhibits nosharp peaks (e.g. exhibits an amorphous halo).

As used herein, the term “stoichiometry” refers to the molar ratio of acombination of two or more components, for example, the molar ratio ofacid or base to compound that form an amorphous complex. For example, a1:1 mixture of acid or base with compound (i.e. 1 mole acid or base permole of compound) resulting in an amorphous solid form has a 1:1stoichiometry.

As used herein, the term “composition” refers to a pharmaceuticalpreparation suitable for administration to an intended subject fortherapeutic purposes that contains at least one pharmaceutically activecompound, including any solid form thereof. The composition may includeat least one pharmaceutically acceptable component to provide animproved formulation of the compound, such as a suitable carrier orexcipient.

As used herein, the term “subject” refers to a living organism that istreated with compounds as described herein, including, but not limitedto, any mammal, such as a human, other primates, sports animals, animalsof commercial interest such as cattle, farm animals such as horses, orpets such as dogs and cats.

As used herein, the term “biopharmaceutical properties” refers to thepharmacokinetic action of a compound or complex of the presentinvention, including the dissolution, absorption and distribution of thecompound on administration to a subject. As such, certain solid forms ofcompounds of the invention, such as amorphous complexes of compounds ofthe invention, are intended to provide improved dissolution andabsorption of the active compound, which is typically reflected inimproved C_(max) (i.e. the maximum achieved concentration in the plasmaafter administration of the drug) and improved AUC (i.e. area under thecurve of drug plasma concentration vs. time after administration of thedrug).

The term “pharmaceutically acceptable” indicates that the indicatedmaterial does not have properties that would cause a reasonably prudentmedical practitioner to avoid administration of the material to apatient, taking into consideration the disease or conditions to betreated and the respective route of administration. For example, it iscommonly required that such a material be essentially sterile, e.g., forinjectibles.

In the present context, the term “therapeutically effective” or“effective amount” indicates that the materials or amount of material iseffective to prevent, alleviate, or ameliorate one or more symptoms of adisease or medical condition, and/or to prolong the survival of thesubject being treated.

In the present context, the terms “synergistically effective” or“synergistic effect” indicate that two or more compounds that aretherapeutically effective, when used in combination, provide improvedtherapeutic effects greater than the additive effect that would beexpected based on the effect of each compound used by itself.

As used herein, the term “modulating” or “modulate” refers to an effectof altering a biological activity (i.e. increasing or decreasing theactivity), especially a biological activity associated with a particularbiomolecule such as a protein kinase. For example, an inhibitor of aparticular biomolecule modulates the activity of that biomolecule, e.g.,an enzyme, by decreasing the activity of the biomolecule, such as anenzyme. Such activity is typically indicated in terms of an inhibitoryconcentration (IC₅₀) of the compound for an inhibitor with respect to,for example, an enzyme.

“Pain” or a “pain condition” can be acute and/or chronic pain,including, without limitation, arachnoiditis; arthritis (e.g.osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout);back pain (e.g. sciatica, ruptured disc, spondylolisthesis,radiculopathy); burn pain; cancer pain; dysmenorrhea; headaches (e.g.migraine, cluster headaches, tension headaches); head and facial pain(e.g. cranial neuralgia, trigeminal neuralgia); hyperalgesia;hyperpathia; inflammatory pain (e.g. pain associated with irritablebowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn'sdisease, cystitis, pain from bacterial, fungal or viral infection);keloid or scar tissue formation; labor or delivery pain; muscle pain(e.g. as a result of polymyositis, dermatomyositis, inclusion bodymyositis, repetitive stress injury (e.g. writer's cramp, carpal tunnelsyndrome, tendonitis, tenosynovitis)); myofascial pain syndromes (e.g.fibromyalgia); neuropathic pain (e.g. diabetic neuropathy, causalgia,entrapment neuropathy, brachial plexus avulsion, occipital neuralgia,gout, reflex sympathetic dystrophy syndrome, phantom limb orpost-amputation pain, postherpetic neuralgia, central pain syndrome, ornerve pain resulting from trauma (e.g. nerve injury), disease (e.g.diabetes, multiple sclerosis, Guillan-Barre Syndrome, myasthenia gravis,neurodegenerative diseases such as Parkinson's disease, Alzheimer'sdisease, amyotrophic lateral sclerosis, or cancer treatment); painassociated with skin disorders (e.g. shingles, herpes simplex, skintumors, cysts, neurofibromatosis); sports injuries (e.g. cuts, sprains,strains, bruises, dislocations, fractures, spinal chord, head); spinalstenosis; surgical pain; tactile allodynia; temporomandibular disorders;vascular disease or injury (e.g. vasculitis, coronary artery disease,reperfusion injury (e.g. following ischemia, stroke, or myocardialinfarcts)); other specific organ or tissue pain (e.g. ocular pain,corneal pain, bone pain, heart pain, visceral pain (e.g. kidney,gallbladder, gastrointestinal), joint pain, dental pain, pelvichypersensitivity, pelvic pain, renal colic, urinary incontinence); otherdisease associated pain (e.g. sickle cell anemia, AIDS, herpes zoster,psoriasis, endometriosis, asthma, chronic obstructive pulmonary disease(COPD), silicosis, pulmonary sarcoidosis, esophagitis, heart burn,gastroesophageal reflux disorder, stomach and duodenal ulcers,functional dyspepsia, bone resorption disease, osteoporosis, cerebralmalaria, bacterial meningitis); or pain due to graft v. host rejectionor allograft rejections.

Kinase Targets and Indications of the Invention

Protein kinases play key roles in propagating biochemical signals indiverse biological pathways. More than 500 kinases have been described,and specific kinases have been implicated in a wide range of diseases orconditions (i.e., indications), including for example withoutlimitation, cancer, cardiovascular disease, inflammatory disease,neurological disease, and other diseases. As such, kinases representimportant control points for small molecule therapeutic intervention.Description of specific target protein kinases contemplated by thepresent invention follow:

A-Raf: Target kinase A-Raf (i.e., v-raf murine sarcoma 3611 viraloncogene homolog 1) is a 67.6 kDa serine/threonine kinase encoded bychromosome Xp11.4-p11.2 (symbol: ARAF). The mature protein comprises RBD(i.e., Ras binding domain) and phorbol-ester/DAG-type zinc finger domainand is involved in the transduction of mitogenic signals from the cellmembrane to the nucleus. A-Raf inhibitors may be useful in treatingneurologic diseases such as multi-infarct dementia, head injury, spinalcord injury, Alzheimer's disease (AD), Parkinson's disease; neoplasticdiseases including, but not limited to, melanoma, glioma, sarcoma,carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal,ovarian), lymphoma (e.g. histiocytic lymphoma), neurofibromatosis,myelodysplastic syndrome, leukemia, tumor angiogenesis; pain ofneuropathic or inflammatory origin, including acute pain, chronic pain,cancer-related pain and migraine; and diseases associated with muscleregeneration or degeneration, including, but not limited to, vascularrestenosis, sarcopenia, muscular dystrophies (including, but not limitedto, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral,Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies),motor neuron diseases (including, but not limited to, amyotrophiclateral sclerosis, infantile progressive spinal muscular atrophy,intermediate spinal muscular atrophy, juvenile spinal muscular atrophy,spinal bulbar muscular atrophy, and adult spinal muscular atrophy),inflammatory myopathies (including, but not limited to, dermatomyositis,polymyositis, and inclusion body myositis), diseases of theneuromuscular junction (including, but not limited to, myastheniagravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome),myopathies due to endocrine abnormalities (including, but not limitedto, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency).

B-Raf: Target kinase B-Raf (i.e., v-raf murine sarcoma viral oncogenehomolog B1) is a 84.4 kDa serine/threonine kinase encoded by chromosome7q34 (symbol: BRAF). The mature protein comprises RBD (i.e., Ras bindingdomain), C1 (i.e., protein kinase C conserved region 1) and STK (i.e.,serine/threonine kinase) domains.

Target kinase B-Raf is involved in the transduction of mitogenic signalsfrom the cell membrane to the nucleus and may play a role in thepostsynaptic responses of hippocampal neurons. As such, genes of the RAFfamily encode kinases that are regulated by Ras and mediate cellularresponses to growth signals. Indeed, B-Raf kinase is a key component ofthe RAS->Raf->MEK->ERK/MAP kinase signaling pathway, which plays afundamental role in the regulation of cell growth, division andproliferation, and, when constitutively activated, causes tumorigenesis.Among several isoforms of Raf kinase, the B-type, or B-Raf, is thestrongest activator of the downstream MAP kinase signaling.

The BRAF gene is frequently mutated in a variety of human tumors,especially in malignant melanoma and colon carcinoma. The most commonreported mutation was a missense thymine (T) to adenine (A) transversionat nucleotide 1796 (T1796A; amino acid change in the B-Raf protein isVal<600> to Glu<600>) observed in 80% of malignant melanoma tumors.Functional analysis reveals that this transversion is the only detectedmutation that causes constitutive activation of B-Raf kinase activity,independent of RAS activation, by converting B-Raf into a dominanttransforming protein. Based on precedents, human tumors developresistance to kinase inhibitors by mutating a specific amino acid in thecatalytic domain as the “gatekeeper”. (Balak, et. al., Clin Cancer Res.2006, 12:6494-501). Mutation of Thr-529 in BRAF to Ile is thusanticipated as a mechanism of resistance to BRAF inhibitors, and thiscan be envisioned as a transition in codon 529 from ACC to ATC.

Niihori et al., report that in 43 individuals withcardio-facio-cutaneous (CFC) syndrome, they identified two heterozygousKRAS mutations in three individuals and eight BRAF mutations in 16individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway isa common molecular basis for the three related disorders (Niihori etal., Nat. Genet. 2006, 38(3):294-6).

c-Raf-1: Target kinase c-Raf-1 (i.e., v-raf murine sarcoma viraloncogene homolog 1) is a 73.0 kDa STK encoded by chromosome 3p25(symbol: RAF1). c-Raf-1 can be targeted to the mitochondria by BCL2(i.e., oncogene B-cell leukemia 2) which is a regulator of apoptoticcell death. Active c-Raf-1 improves BCL2-mediated resistance toapoptosis, and c-Raf-1 phosphorylates BAD (i.e., BCL2-binding protein).c-Raf-1 is implicated in carcinomas, including colorectal, ovarian, lungand renal cell carcinoma. c-Raf-1 is also implicated as an importantmediator of tumor angiogenesis (Hood, J. D. et al., 2002, Science 296,2404). c-Raf-1 inhibitors may also be useful for the treatment of acutemyeloid leukemia and myelodysplastic syndromes (Crump, Curr Pharm Des2002, 8(25):2243-8). Raf-1 activators may be useful as treatment forneuroendocrine tumors, such as medullary thyroid cancer, carcinoid,small cell lung cancer and pheochromocytoma (Kunnimalaiyaan et al.,Anticancer Drugs 2006, 17(2):139-42).

A-Raf, B-Raf and/or c-Raf-1 inhibitors may be useful in treatingA-Raf-mediated, B-Raf-mediated or c-Raf-1-mediated disease or conditionselected from the group consisting of neurologic diseases, including,but not limited to, multi-infarct dementia, head injury, spinal cordinjury, Alzheimer's disease (AD), Parkinson's disease, seizures andepilepsy; neoplastic diseases including, but not limited to, melanoma,glioma, glioblastoma multiforme, pilocytic astrocytoma, sarcoma,carcinoma (e.g. gastrointestinal, liver, biliary tract (e.g. bile duct,cholangiocarcinoma), colorectal, lung, gallbladder, breast, pancreatic,thyroid, renal, ovarian, adrenocortical, prostate), lymphoma (e.g.histiocytic lymphoma) neurofibromatosis, acute myeloid leukemia,myelodysplastic syndrome, leukemia, tumor angiogenesis, gastrointestinalstromal tumors, neuroendocrine tumors such as medullary thyroid cancer,carcinoid, small cell lung cancer, Kaposi's sarcoma, andpheochromocytoma; pain of neuropathic or inflammatory origin, including,but not limited to, acute pain, chronic pain, cancer-related pain, andmigraine; cardiovascular diseases including, but not limited to, heartfailure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g.thrombotic microangiopathy syndromes), atherosclerosis, and reperfusioninjury; inflammation and/or proliferation including, but not limited to,psoriasis, eczema, arthritis and autoimmune diseases and conditions,osteoarthritis, endometriosis, scarring, vascular restenosis, fibroticdisorders, rheumatoid arthritis, inflammatory bowel disease (IBD);immunodeficiency diseases, including, but not limited to, organtransplant rejection, graft versus host disease, and Kaposi's sarcomaassociated with HIV; renal cystic, or prostatic diseases, including, butnot limited to, diabetic nephropathy, polycystic kidney disease,nephrosclerosis, glomerulonephritis, prostate hyperplasia, polycysticliver disease, tuberous sclerosis, Von Hippel Lindau disease, medullarycystic kidney disease, nephronophthisis, and cystic fibrosis; metabolicdisorders, including, but not limited to, obesity; infection, including,but not limited to Helicobacter pylori, Hepatitis and Influenza viruses,fever, HIV and sepsis; pulmonary diseases including, but not limited to,chronic obstructive pulmonary disease (COPD) and acute respiratorydistress syndrome (ARDS); genetic developmental diseases, including, butnot limited to, Noonan's syndrome, Costello syndrome,(faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faciocutaneoussyndrome (CFC), and neural crest syndrome abnormalities causingcardiovascular, skeletal, intestinal, skin, hair and endocrine diseases;and diseases associated with muscle regeneration or degeneration,including, but not limited to, sarcopenia, muscular dystrophies(including, but not limited to, Duchenne, Becker, Emery-Dreifuss,Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal andCongenital Muscular Dystrophies), motor neuron diseases (including, butnot limited to, amyotrophic lateral sclerosis, infantile progressivespinal muscular atrophy, intermediate spinal muscular atrophy, juvenilespinal muscular atrophy, spinal bulbar muscular atrophy, and adultspinal muscular atrophy), inflammatory myopathies (including, but notlimited to, dermatomyositis, polymyositis, and inclusion body myositis),diseases of the neuromuscular junction (including, but not limited to,myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenicsyndrome), myopathies due to endocrine abnormalities (including, but notlimited to, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency).

Alternative Compound Forms or Derivatives

Compounds P-0001 or P-0002 contemplated herein are described withreference to the specific compounds. In addition, P-0001 or P-0002 mayexist in a number of different forms or derivatives, all within thescope of the present invention. Alternative forms or derivatives,include, for example, (a) prodrugs, and active metabolites (b) tautomers(c) pharmaceutically acceptable salts and (d) solid forms, includingdifferent crystal forms, polymorphic or amorphous solids, includinghydrates and solvates thereof, and other forms.

(a) Prodrugs and Metabolites

In addition to compounds P-0001 or P-0002 described herein, theinvention also includes prodrugs (generally pharmaceutically acceptableprodrugs), active metabolic derivatives (active metabolites), and theirpharmaceutically acceptable salts.

Prodrugs are compounds or pharmaceutically acceptable salts thereofwhich, when metabolized under physiological conditions or when convertedby solvolysis, yield the desired active compound. Prodrugs include,without limitation, esters, amides, carbamates, carbonates, ureides,solvates, or hydrates of the active compound. Typically, the prodrug isinactive, or less active than the active compound, but may provide oneor more advantageous handling, administration, and/or metabolicproperties. Prodrugs may include variants wherein an —NH group of thecompound has undergone acylation, such as the 1-position of thepyrrolo[2,3-b]pyridine ring or the nitrogen of the sulfonamide group ofeither of P-0001 or P-0002, where cleavage of the acyl group providesthe free —NH group of the active drug. Some prodrugs are activatedenzymatically to yield the active compound, or a compound may undergofurther chemical reaction to yield the active compound. Prodrugs mayproceed from prodrug form to active form in a single step or may haveone or more intermediate forms which may themselves have activity or maybe inactive.

As described in The Practice of Medicinal Chemistry, Ch. 31-32 (Ed.Wermuth, Academic Press, San Diego, Calif., 2001), prodrugs can beconceptually divided into two non-exclusive categories, bioprecursorprodrugs and carrier prodrugs. Generally, bioprecursor prodrugs arecompounds that are inactive or have low activity compared to thecorresponding active drug compound, that contain one or more protectivegroups and are converted to an active form by metabolism or solvolysis.Both the active drug form and any released metabolic products shouldhave acceptably low toxicity. Typically, the formation of active drugcompound involves a metabolic process or reaction that is one of thefollowing types:

Oxidative reactions: Oxidative reactions are exemplified withoutlimitation by reactions such as oxidation of alcohol, carbonyl, and acidfunctionalities, hydroxylation of aliphatic carbons, hydroxylation ofalicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation ofcarbon-carbon double bonds, oxidation of nitrogen-containing functionalgroups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidativeN-dealkylation, oxidative O- and S-dealkylation, oxidative deamination,as well as other oxidative reactions.

Reductive reactions: Reductive reactions are exemplified withoutlimitation by reactions such as reduction of carbonyl functionalities,reduction of alcohol functionalities and carbon-carbon double bonds,reduction of nitrogen-containing functional groups, and other reductionreactions.

Reactions without change in the oxidation state: Reactions withoutchange in the state of oxidation are exemplified without limitation byreactions such as hydrolysis of esters and ethers, hydrolytic cleavageof carbon-nitrogen single bonds, hydrolytic cleavage of non-aromaticheterocycles, hydration and dehydration at multiple bonds, new atomiclinkages resulting from dehydration reactions, hydrolyticdehalogenation, removal of hydrogen halide molecule, and other suchreactions.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improves uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, the prodrug and anyrelease transport moiety are acceptably non-toxic. For prodrugs wherethe transport moiety is intended to enhance uptake, typically therelease of the transport moiety should be rapid. In other cases, it isdesirable to utilize a moiety that provides slow release, e.g., certainpolymers or other moieties, such as cyclodextrins. (See, e.g., Cheng etal., U.S. Patent Publ. No. 20040077595, application Ser. No. 10/656,838,incorporated herein by reference.) Such carrier prodrugs are oftenadvantageous for orally administered drugs. In some instances, thetransport moiety provides targeted delivery of the drug, for example thedrug may be conjugated to an antibody or antibody fragment. Carrierprodrugs can, for example, be used to improve one or more of thefollowing properties: increased lipophilicity, increased duration ofpharmacological effects, increased site-specificity, decreased toxicityand adverse reactions, and/or improvement in drug formulation (e.g.,stability, water solubility, suppression of an undesirable organolepticor physiochemical property). For example, lipophilicity can be increasedby esterification of hydroxyl groups with lipophilic carboxylic acids,or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols.Wermuth, supra.

Metabolites, e.g., active metabolites, overlap with prodrugs asdescribed above, e.g., bioprecursor prodrugs. Thus, such metabolites arepharmacologically active compounds or compounds that further metabolizeto pharmacologically active compounds that are derivatives resultingfrom metabolic processes in the body of a subject. Of these, activemetabolites are such pharmacologically active derivative compounds. Forprodrugs, the prodrug compound is generally inactive or of loweractivity than the metabolic product. For active metabolites, the parentcompound may be either an active compound or may be an inactive prodrug.For example, in some compounds, one or more alkoxy groups can bemetabolized to hydroxyl groups while retaining pharmacologic activityand/or carboxyl groups can be esterified, e.g., glucuronidation. In somecases, there can be more than one metabolite, where an intermediatemetabolite(s) is further metabolized to provide an active metabolite.For example, in some cases a derivative compound resulting frommetabolic glucuronidation may be inactive or of low activity, and can befurther metabolized to provide an active metabolite.

Metabolites of a compound may be identified using routine techniquesknown in the art, and their activities determined using tests such asthose described herein. See, e.g., Bertolini et al., 1997, J. Med.Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci 86(7):756-757;Bagshawe, 1995, Drug Dev. Res., 34:220-230; Wermuth, supra.

(b) Tautomers

It is understood that some compounds may exhibit tautomerism. In suchcases, the formulae provided herein expressly depict only one of thepossible tautomeric forms. It is therefore to be understood thatcompounds P-0001 or P-0002 provided herein are intended to represent anytautomeric form of the depicted compound and is not to be limited merelyto the specific tautomeric form depicted by the drawing of the compound.

(c) Pharmaceutically Acceptable Salts

Unless specified to the contrary, specification of compounds P-0001 orP-0002 herein includes pharmaceutically acceptable salts of suchcompound. Thus, compounds P-0001 or P-0002 can be in the form ofpharmaceutically acceptable salts, or can be formulated aspharmaceutically acceptable salts. Contemplated pharmaceuticallyacceptable salt forms include, without limitation, mono, bis, tris,tetrakis, and so on. Pharmaceutically acceptable salts are non-toxic inthe amounts and concentrations at which they are administered. Thepreparation of such salts can facilitate the pharmacological use byaltering the physical characteristics of a compound without preventingit from exerting its physiological effect. Useful alterations inphysical properties include lowering the melting point to facilitatetransmucosal administration and increasing the solubility to facilitateadministering higher concentrations of the drug. Compounds P-0001 orP-0002 possess a sufficiently acidic and a sufficiently basic functionalgroup, and accordingly can react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt.

Pharmaceutically acceptable salts include acid addition salts such asthose containing chloride, bromide, iodide, hydrochloride, acetate,phenylacetate, acrylate, ascorbate, aspartate, benzoate,2-phenoxybenzoate, 2-acetoxybenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzoate, methylbenzoate, bicarbonate, butyne-1,4 dioate,hexyne-1,6-dioate, caproate, caprylate, chlorobenzoate, cinnamate,citrate, decanoate, formate, fumarate, glycolate, gluconate, glucarate,glucuronate, glucose-6-phosphate, glutamate, heptanoate, hexanoate,isethionate, isobutyrate, gamma-hydroxybutyrate, phenylbutyrate,lactate, malate, maleate, hydroxymaleate, methylmaleate, malonate,mandelate, nicotinate, nitrate, isonicotinate, octanoate, oleate,oxalate, pamoate, phosphate, monohydrogenphosphate, dihydrogenphosphate,orthophosphate, metaphosphate, pyrophosphate, 2-phosphoglycerate,3-phosphoglycerate, phthalate, propionate, phenylpropionate, propiolate,pyruvate, quinate, salicylate, 4-aminosalicylate, sebacate, stearate,suberate, succinate, sulfate, pyrosulfate, bisulfate, sulfite,bisulfite, sulfamate, sulfonate, benzenesulfonate (i.e. besylate),ethanesulfonate (i.e. esylate), ethane-1,2-disulfonate,2-hydroxyethanesulfonate (i.e. isethionate), methanesulfonate (i.e.mesylate), naphthalene-1-sulfonate, naphthalene-2-sulfonate (i.e.napsylate), propanesulfonate, p-toluenesulfonate (i.e. tosylate),xylenesulfonates, cyclohexylsulfamate, tartrate, and trifluoroacetate.These pharmaceutically acceptable acid addition salts can be preparedusing the appropriate corresponding acid.

When acidic functional groups, such as carboxylic acid or phenol arepresent, pharmaceutically acceptable salts also include basic additionsalts such as those containing benzathine, chloroprocaine, choline,ethanolamine, diethanolamine, triethanolamine, t-butylamine,dicyclohexylamine, ethylenediamine, N,N′-dibenzylethylenediamine,meglumine, hydroxyethylpyrrolidine, piperidine, morpholine, piperazine,procaine, aluminum, calcium, copper, iron, lithium, magnesium,manganese, potassium, sodium, zinc, ammonium, and mono-, di-, ortri-alkylamines (e.g. diethylamine), or salts derived from amino acidssuch as L-histidine, L-glycine, L-lysine, and L-arginine. For example,see Remington's Pharmaceutical Sciences, 19^(th) ed., Mack PublishingCo., Easton, Pa., Vol. 2, p. 1457, 1995. These pharmaceuticallyacceptable base addition salts can be prepared using the appropriatecorresponding base.

Pharmaceutically acceptable salts can be prepared by standardtechniques. For example, the free-base form of a compound can bedissolved in a suitable solvent, such as an aqueous or aqueous-alcoholsolution containing the appropriate acid and then isolated byevaporating the solution. In another example, a salt can be prepared byreacting the free base and acid in an organic solvent. If the particularcompound is an acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an appropriate inorganic or organic base.

(d) Other Compound Forms

In the case of agents that are solids, it is understood by those skilledin the art that the compounds and salts may exist in different crystalor polymorphic forms, or may be formulated as co-crystals, or may be inan amorphous form, or may be any combination thereof (e.g. partiallycrystalline, partially amorphous, or mixtures of polymorphs) all ofwhich are intended to be within the scope of the present invention andspecified formulae. Whereas salts are formed by acid/base addition, i.e.a free base or free acid of the compound of interest forms an acid/basereaction with a corresponding addition base or addition acid,respectively, resulting in an ionic charge interaction, co-crystals area new chemical species that is formed between neutral compounds,resulting in the compound and an additional molecular species in thesame crystal structure.

In some instances, either of compounds P-0001 or P-0002 is complexedwith an acid or a base, including base addition salts such as ammonium,diethylamine, ethanolamine, ethylenediamine, diethanolamine,t-butylamine, piperazine, meglumine; acid addition salts, such asacetate, acetylsalicylate, besylate, camsylate, citrate, formate,fumarate, glutarate, hydrochlorate, maleate, mesylate, nitrate, oxalate,phosphate, succinate, sulfate, tartrate, thiocyanate and tosylate; andamino acids such as alanine, arginine, asparagine, aspartic acid,cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine,leucine, lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine or valine. In combining either of compounds P-0001or P-0002 with the acid or base, an amorphous complex is preferablyformed rather than a crystalline material such as a typical salt orco-crystal. In some instances, the amorphous form of the complex isfacilitated by additional processing, such as by spray-drying,mechanochemical methods such as roller compaction, or microwaveirradiation of the parent compound mixed with the acid or base. Suchamorphous complexes provide several advantages. For example, lowering ofthe melting temperature relative to the free base facilitates additionalprocessing, such as hot melt extrusion, to further improve thebiopharmaceutical properties of the compound. Also, the amorphouscomplex is readily friable, which provides improved compression forloading of the solid into capsule or tablet form.

Additionally, either of compounds P-0001 or P-0002 are intended to coverhydrated or solvated as well as unhydrated or unsolvated forms of theidentified material. For example, either of compounds P-0001 or P-0002or salts thereof includes both hydrated and non-hydrated forms. Otherexamples of solvates include either of compounds P-0001 or P-0002 incombination with a suitable solvent, such as isopropanol, ethanol,methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

Formulations and Administration

Either of compounds P-0001 or P-0002 or any form thereof as describedherein will typically be used in therapy for human subjects. However,either of compounds P-0001 or P-0002 and compositions thereof may alsobe used to treat similar or identical indications in other animalsubjects, and can be administered by different routes, includinginjection (i.e. parenteral, including intravenous, intraperitoneal,subcutaneous, and intramuscular), oral, transdermal, transmucosal,rectal, or inhalant. Such dosage forms should allow the compound toreach target cells. Other factors are well known in the art, and includeconsiderations such as toxicity and dosage forms that retard thecompound or composition from exerting its effects. Techniques andformulations generally may be found in Remington: The Science andPractice of Pharmacy, 21^(st) edition, Lippincott, Williams and Wilkins,Philadelphia, Pa., 2005 (hereby incorporated by reference herein).

In some embodiments, compositions will comprise pharmaceuticallyacceptable carriers or excipients, such as fillers, binders,disintegrants, glidants, lubricants, complexing agents, solubilizers,and surfactants, which may be chosen to facilitate administration of thecompound by a particular route. Examples of carriers include calciumcarbonate, calcium phosphate, various sugars such as lactose, glucose,or sucrose, types of starch, cellulose derivatives, gelatin, lipids,liposomes, nanoparticles, and the like. Carriers also includephysiologically compatible liquids as solvents or for suspensions,including, for example, sterile solutions of water for injection (WFI),saline solution, dextrose solution, Hank's solution, Ringer's solution,vegetable oils, mineral oils, animal oils, polyethylene glycols, liquidparaffin, and the like. Excipients may also include, for example,colloidal silicon dioxide, silica gel, talc, magnesium silicate, calciumsilicate, sodium aluminosilicate, magnesium trisilicate, powderedcellulose, macrocrystalline cellulose, carboxymethyl cellulose,cross-linked sodium carboxymethylcellulose, sodium benzoate, calciumcarbonate, magnesium carbonate, stearic acid, aluminum stearate, calciumstearate, magnesium stearate, zinc stearate, sodium stearyl fumarate,syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate,glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate,hydrogenated vegetable oil, hydrogenated cotton seed oil, castor seedoil mineral oil, polyethylene glycol (e.g. PEG 4000-8000),polyoxyethylene glycol, poloxamers, povidone, crospovidone,croscarmellose sodium, alginic acid, casein, methacrylic aciddivinylbenzene copolymer, sodium docusate, cyclodextrins (e.g.2-hydroxypropyl-.delta.-cyclodextrin), polysorbates (e.g. polysorbate80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000succinate), magnesium lauryl sulfate, sodium lauryl sulfate,polyethylene glycol ethers, di-fatty acid ester of polyethylene glycols,or a polyoxyalkylene sorbitan fatty acid ester (e.g., polyoxyethylenesorbitan ester Tween®), polyoxyethylene sorbitan fatty acid esters,sorbitan fatty acid ester, e.g. a sorbitan fatty acid ester from a fattyacid such as oleic, stearic or palmitic acid, mannitol, xylitol,sorbitol, maltose, lactose, lactose monohydrate or lactose spray dried,sucrose, fructose, calcium phosphate, dibasic calcium phosphate,tribasic calcium phosphate, calcium sulfate, dextrates, dextran,dextrin, dextrose, cellulose acetate, maltodextrin, simethicone,polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl methylcelluloses), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, andthe like.

In some embodiments, oral administration may be used. Pharmaceuticalpreparations for oral use can be formulated into conventional oraldosage forms such as capsules, tablets, and liquid preparations such assyrups, elixirs, and concentrated drops. Either of compounds P-0001 orP-0002 may be combined with solid excipients, optionally grinding aresulting mixture, and processing the mixture of granules, after addingsuitable auxiliaries, if desired, to obtain, for example, tablets,coated tablets, hard capsules, soft capsules, solutions (e.g. aqueous,alcoholic, or oily solutions) and the like. Suitable excipients are, inparticular, fillers such as sugars, including lactose, glucose, sucrose,mannitol, or sorbitol; cellulose preparations, for example, corn starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP:povidone); oily excipients, including vegetable and animal oils, such assunflower oil, olive oil, or codliver oil. The oral dosage formulationsmay also contain disintegrating agents, such as cross-linkedpolyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such assodium alginate; a lubricant, such as talc or magnesium stearate; aplasticizer, such as glycerol or sorbitol; a sweetening agent such assucrose, fructose, lactose, or aspartame; a natural or artificialflavoring agent, such as peppermint, oil of wintergreen, or cherryflavoring; or dye-stuffs or pigments, which may be used foridentification or characterization of different doses or combinations.Also provided are dragee cores with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally contain,for example, gum arabic, talc, poly-vinylpyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin (“gelcaps”), as well as soft, sealed capsulesmade of gelatin, and a plasticizer, such as glycerol or sorbitol. Thepush-fit capsules can contain the active ingredients in admixture withfiller such as lactose, binders such as starches, and/or lubricants suchas talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compound may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols.

In some embodiments, injection (parenteral administration) may be used,e.g., intramuscular, intravenous, intraperitoneal, and/or subcutaneous.Either of compounds P-0001 or P-0002 and compositions thereof forinjection may be formulated in sterile liquid solutions, preferably inphysiologically compatible buffers or solutions, such as salinesolution, Hank's solution, or Ringer's solution. Dispersions may also beprepared in non-aqueous solutions, such as glycerol, propylene glycol,ethanol, liquid polyethylene glycols, triacetin, and vegetable oils.Solutions may also contain a preservative, such as methylparaben,propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, and thelike. In addition, either of compounds P-0001 or P-0002 or compositionsthereof may be formulated in solid form, including, for example,lyophilized forms, and redissolved or suspended prior to use.

In some embodiments, transmucosal, topical or transdermal administrationmay be used. In such formulations of either of compounds P-0001 orP-0002, penetrants appropriate to the barrier to be permeated are used.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, bile salts and fusidic acidderivatives. In addition, detergents may be used to facilitatepermeation. Transmucosal administration, for example, may be throughnasal sprays or suppositories (rectal or vaginal). Compositions ofeither of compounds P-0001 or P-0002 for topical administration may beformulated as oils, creams, lotions, ointments, and the like by choiceof appropriate carriers known in the art. Suitable carriers includevegetable or mineral oils, white petrolatum (white soft paraffin),branched chain fats or oils, animal fats and high molecular weightalcohol (greater than C₁₂). In some embodiments, carriers are selectedsuch that the active ingredient is soluble. Emulsifiers, stabilizers,humectants and antioxidants may also be included as well as agentsimparting color or fragrance, if desired. Creams for topical applicationare preferably formulated from a mixture of mineral oil,self-emulsifying beeswax and water in which mixture the activeingredient, dissolved in a small amount of solvent (e.g., an oil), isadmixed. Additionally, administration by transdermal means may comprisea transdermal patch or dressing such as a bandage impregnated with anactive ingredient and optionally one or more carriers or diluents knownin the art. To be administered in the form of a transdermal deliverysystem, the dosage administration will be continuous rather thanintermittent throughout the dosage regimen.

In some embodiments, either of compounds P-0001 or P-0002 orcompositions thereof are administered as inhalants. Either of compoundsP-0001 or P-0002 or compositions thereof may be formulated as dry powderor a suitable solution, suspension, or aerosol. Powders and solutionsmay be formulated with suitable additives known in the art. For example,powders may include a suitable powder base such as lactose or starch,and solutions may comprise propylene glycol, sterile water, ethanol,sodium chloride and other additives, such as acid, alkali and buffersalts. Such solutions or suspensions may be administered by inhaling viaspray, pump, atomizer, or nebulizer, and the like. Either of compoundsP-0001 or P-0002 or compositions thereof may also be used in combinationwith other inhaled therapies, for example corticosteroids such asfluticasone proprionate, beclomethasone dipropionate, triamcinoloneacetonide, budesonide, and mometasone furoate; beta agonists such asalbuterol, salmeterol, and formoterol; anticholinergic agents such asipratroprium bromide or tiotropium; vasodilators such as treprostinaland iloprost; enzymes such as DNAase; therapeutic proteins;immunoglobulin antibodies; an oligonucleotide, such as single or doublestranded DNA or RNA, siRNA; antibiotics such as tobramycin; muscarinicreceptor antagonists; leukotriene antagonists; cytokine antagonists;protease inhibitors; cromolyn sodium; nedocril sodium; and sodiumcromoglycate.

The amounts of either of compounds P-0001 or P-0002 or compositionsthereof to be administered can be determined by standard procedurestaking into account factors such as the compound activity (in vitro,e.g. the compound IC₅₀ vs. target, or in vivo activity in animalefficacy models), pharmacokinetic results in animal models (e.g.biological half-life or bioavailability), the age, size, and weight ofthe subject, and the disorder associated with the subject. Theimportance of these and other factors are well known to those ofordinary skill in the art. Generally, a dose will be in the range ofabout 0.01 to 50 mg/kg, also about 0.1 to 20 mg/kg of the subject beingtreated. Multiple doses may be used.

Either of compounds P-0001 or P-0002 or compositions thereof may also beused in combination with other therapies for treating the same disease.Such combination use includes administration of either of compoundsP-0001 or P-0002 and one or more other therapeutics at different times,or co-administration of either of compounds P-0001 or P-0002 and one ormore other therapies. In some embodiments, dosage may be modified foreither of compounds P-0001 or P-0002 or other therapeutics used incombination, e.g., reduction in the amount dosed relative to a compoundor therapy used alone, by methods well known to those of ordinary skillin the art.

It is understood that use in combination includes use with othertherapies, drugs, medical procedures etc., where the other therapy orprocedure may be administered at different times (e.g. within a shorttime, such as within hours (e.g. 1, 2, 3, 4-24 hours), or within alonger time (e.g. 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)) than eitherof compounds P-0001 or P-0002 or compositions thereof, or at the sametime as either of compounds P-0001 or P-0002 or compositions thereof.Use in combination also includes use with a therapy or medical procedurethat is administered once or infrequently, such as surgery, along witheither of compounds P-0001 or P-0002 or compositions thereofadministered within a short time or longer time before or after theother therapy or procedure. In some embodiments, the present inventionprovides for delivery of either of compounds P-0001 or P-0002 orcompositions thereof and one or more other drug therapeutics deliveredby a different route of administration or by the same route ofadministration. The use in combination for any route of administrationincludes delivery of either of compounds P-0001 or P-0002 orcompositions thereof and one or more other drug therapeutics deliveredby the same route of administration together in any formulation,including formulations where the two compounds are chemically linked insuch a way that they maintain their therapeutic activity whenadministered. In one aspect, the other drug therapy may beco-administered with either of compounds P-0001 or P-0002 orcompositions thereof. Use in combination by co-administration includesadministration of co-formulations or formulations of chemically joinedcompounds, or administration of two or more compounds in separateformulations within a short time of each other (e.g. within an hour, 2hours, 3 hours, up to 24 hours), administered by the same or differentroutes. Co-administration of separate formulations includesco-administration by delivery via one device, for example the sameinhalant device, the same syringe, etc., or administration from separatedevices within a short time of each other. Co-formulations of either ofcompounds P-0001 or P-0002 and one or more additional drug therapiesdelivered by the same route includes preparation of the materialstogether such that they can be administered by one device, including theseparate compounds combined in one formulation, or compounds that aremodified such that they are chemically joined, yet still maintain theirbiological activity. Such chemically joined compounds may have a linkagethat is substantially maintained in vivo, or the linkage may break downin vivo, separating the two active components.

EXAMPLES

Examples related to the present invention are described below. In mostcases, alternative techniques can be used. The examples are intended tobe illustrative and are not limiting or restrictive to the scope of theinvention. In some examples, the mass spectrometry result indicated fora compound may have more than one value due to the isotope distributionof an atom in the molecule, such as a compound having a bromo or chlorosubstituent. Synthesis of known compounds for formation of solid formscan be found, for example, in U.S. patent application Ser. No.11/473,347 (see also, PCT publication WO2007002433), and U.S. patentapplication Ser. No. 11/960,590 (Publication number 2008/0167338), thedisclosures of which are hereby incorporated by reference regardingmethods of making compounds.

Example 1 Synthesis ofN-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamideP-0001

N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamideP-0001 was synthesized in four steps from 2,4-difluoro-phenylamine 1 asshown in Scheme 1.

Step 1—Preparation ofN-(2,4-difluoro-phenyl)-4-trifluoromethyl-benzenesulfonamide (3)

To 2,4-difluoro-phenylamine (1, 2.09 mL, 20.7 mmol) in 13.04 mL ofdichloromethane, pyridine (0.522 mL, 6.45 mmol) was added and themixture was stirred under nitrogen for 20 minutes.4-Trifluoromethyl-benzenesulfonyl chloride (2, 5.00 g, 20.4 mmol) wasadded slowly and the reaction was stirred overnight. The reactionmixture was treated with 2 mL of 1 M hydrochloric acid in diethyl etherand allowed to sit for 1 hour. The solid precipitate was filtered off,and the filtrate was extracted with 1 N aqueous hydrochloric acidfollowed by brine. The organic portion was dried over magnesium sulfate,filtered and the filtrate was concentrated under vacuum. The resultingsolid was treated with dichloromethane, and the solid was collected anddried to provide the desired compound as a white solid (3, 2.383 g).

Step 2—Preparation ofN-(2,4-difluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide(4)

Into a round bottom flask containing N,N-diisopropylamine (2.692 mL,19.21 mmol) in 50.0 mL or tetrahydrofuran, n-butyllithium (2.50 M inhexane, 7.684 mL, 19.21 mmol) was added at −78° C. under an atmosphereof nitrogen. After stirring at −78° C. for 30 minutes,N-(2,4-difluoro-phenyl)-4-trifluoromethyl-benzenesulfonamide (3, 2.09 g,6.20 mmol) was added, with continued stirring at −78° C. under nitrogenfor one hour. The reaction was allowed to come to room temperature over15 minutes, then poured into water, acidified with 1 N aqueoushydrochloric acid to pH=1, and extracted with ethyl acetate. The organiclayers were combined and washed with brine, then dried over sodiumsulfate, filtered and the filtrate concentrated under vacuum. Theresulting material was purified by silica gel column chromatography, theappropriate fractions were combined, and the solvents removed to providethe desired compound (4, 1.02 g). MS (ESI) [M−H⁺]⁻=364.1.

Step 3—Preparation ofN-{3-[(4-Cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-4-trifluoromethyl-benzenesulfonamide(6)

Into a round bottom flask 1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (5,0.054 g, 0.38 mmol),N-(2,4-difluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide(4, 0.179 g, 0.49 mmol), 0.75 mL of methanol and potassium hydroxide(0.103 g, 1.89 mmol) were combined. The reaction was stirred at roomtemperature for 46 hours, then neutralized with 0.1 N aqueoushydrochloric acid and extracted 3× with ethyl acetate. The organiclayers were combined and washed with brine, then dried over sodiumsulfate, filtered and the filtrate concentrated under vacuum. Thematerial was purified by silica gel column chromatography eluting withethyl acetate and hexane. The appropriate fractions were combined andthe solvent removed under vacuum to provide the desired compound (6,0.018 g). MS (ESI) [M+H⁺]⁺=509.1.

Step 4—Preparation ofN-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide(P-0001)

ToN-{3-[(4-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-4-trifluoromethyl-benzenesulfonamide(6, 15 mg, 0.030 mmol) dissolved in 0.2 mL of tetrahydrofuran,Dess-Martin periodinane (13.8 mg, 0.0324 mmol) was added. The reactionmixture was stirred at room temperature for one hour. The reactionmixture was poured into saturated sodium thiosulfate, the organic layerseparated and washed with brine, then dried over sodium sulfate andfiltered. The filtrate was concentrated under vacuum and the resultingmaterial was purified by silica gel column chromatography, eluting withethyl acetate and hexane. The appropriate fractions were combined andthe solvent removed under vacuum to provide the desired compound(P-0001, 4 mg). MS (ESI) [M−H⁺]⁻=505.5.

Example 2 Synthesis ofN-[3-(4-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamideP-0002

N-[3-(4-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamideP-0002 was synthesized in four steps from 2,4-difluoro-phenylamine 1 asshown in Scheme 2.

Step 1—Preparation ofN-(2,4-difluoro-phenyl)-4-trifluoromethyl-benzenesulfonamide (3)

Per Scheme 1.

Step 2—Preparation ofN-(2,4-difluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide(4)

Per Scheme 1.

Step 3—Preparation ofN-{3-[(4-Ethynyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-4-trifluoromethyl-benzenesulfonamide(8)

Into a round bottom flask4-trimethylsilanylethynyl-1H-pyrrolo[2,3-b]pyridine (7, 0.250 g, 1.17mmol),N-(2,4-difluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide(4, 0.498 g, 1.36 mmol), and 2.0 mL of methanol were added and thesuspension was stirred for 10 minutes. Potassium hydroxide (0.213 g,3.79 mmol) was added and the reaction was stirred at room temperaturefor 6 hours. The reaction was poured into 25 mL of water and 25 mL ofsaturated ammonium chloride, then extracted with 50 mL or ethyl acetate.The organic layer was isolated and concentrated under vacuum. Theresidue was purified by silica gel column chromatography, eluting with agradient of 5 to 60% ethyl acetate in hexanes. The appropriate fractionswere combined and the solvents removed under vacuum to provide thedesired compound (8, 0.146 g).

Step 4—Preparation ofN-[3-(4-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide(P-0002)

ToN-{3-[(4-ethynyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-4-trifluoromethyl-benzenesulfonamide(8, 0.146 g, 0.288 mmol) dissolved in 15 mL of tetrahydrofuran,Dess-Martin periodinane (0.122 g, 0.288 mmol) was added. The reactionmixture was stirred at room temperature for 15 minutes. The reactionmixture was poured into water, extracted with ethyl acetate, and theorganic layer separated and washed with brine, then dried over magnesiumsulfate and filtered. The filtrate was concentrated under vacuum and theresulting material was purified by silica gel column chromatography,eluting with 0 to 30% ethyl acetate and hexane. The appropriatefractions were combined and the solvent removed under vacuum, and thismaterial was further purified by silica gel column chromatography,eluting with 0 to 15% ethyl acetate and hexane. The appropriatefractions were combined and the solvent removed under vacuum to providethe desired compound (P-0001, 121 mg). MS (ESI) [M+H⁺]⁺=506.

Example 3 Salt Forms of Compounds P-0001 or P-0002

P-0001 or P-0002 are characterized as having functionalities providingboth weakly basic and weakly acidic centers which can form organic saltcomplexes, resulting in improved solubility. For example, the N-7 of thepyrrolo[2,3-b]pyridine portion is weakly basic (pKa approximately 4-5)while the sulfonamide nitrogen is weakly acidic (pKa approximately 7).Due to the weakly basic and weakly acidic centers, salts or saltcomplexes may be prepared by either acid addition or base addition.

Base addition salts, preferably organic base addition salts, includingammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine,t-butylamine, piperazine, meglumine, L-arginine, L-histidine, andL-lysine are formed by dissolving P-0001 or P-0002 in 20-50 solventvolumes of an alcohol (such as methanol, ethanol, isopropanol) or othersuitable solvent, such as acetone, with moderate heating (30-35° C.).The suspension is stirred, and 1 equivalent of the base that has beentriturated in a separate portion of the solvent is added. The mixture isstirred under an inert atmosphere until a clear solution is formed. Thesolution is filtered and the solvent removed from the filtrate underreduced pressure. The resulting film forms a friable solid upon vacuumdrying. Alternatively, the salt form is precipitated by addition of coldsolvent such as heptane, methyl t-butyl ether, ethyl acetate or the liketo the solution, the resulting solid filtered and vacuum dried toisolate the friable solid. The resulting solid is assessed for physicalproperties including DSC, XRPD, solubility and intrinsic dissolution.

Acid addition salts, preferably organic acid addition salts, includingacetate, besylate, camsylate, formate, fumarate, maleate, mesylate,nitrate, oxalate, tartrate, thiocyanate, and tosylate are formed byadding P-0001 or P-0002 to 20-50 solvent volumes of acetone (or othersuitable solvent) with stirring and heating (30-35° C.), followed by theaddition of 1 equivalent of the acid. The solution is slowly cooled to2-8° C. and the solid is isolated by either filtration orcentrifugation, followed by vacuum drying. The resulting solid isassessed for physical properties including DSC, XRPD, solubility andintrinsic dissolution.

Additional organic acid salts or salt complexes, including citric acid,tartaric acid, succinic acid, glutaric acid and acetylsalicylic acidsalts or salt complexes of P-0001 or P-0002 are formed in 1:1 or 1:2compound:acid ratios in a suitable solvent such as methanol. P-0001 orP-0002 is added to 15-20 solvent volumes of methanol, with the desiredsolid isolated by either spray drying or by addition of non-solvent suchas heptane followed by filtration and vacuum drying. The resulting solidis assessed for physical properties including DSC, XRPD, solubility andintrinsic dissolution.

Mineral acids, including sulfate, phosphate and hydrochloric acid saltsof P-0001 or P-0002 are prepared from methanol or ethyl acetatesolutions.

The resulting salts or salt complexes may also be processed to provide apreferred amorphous form, such as through spray-drying techniques ormicroprecipitated bulk processing, or may be processed with suitableexcipient materials to provide for a directly compressible orencapsulated dosage form. Salts or salt complexes may also be achievedby mechanochemical (e.g. roller compaction) or microwave irradiation ofthe parent compound with the appropriate selection of charge transferpartner. Such an approach is used to minimize solvent utilization,increase yield, purity and throughput, as well as achieve constructs notattainable using conventional solvent techniques.

Example 4 Compound Properties

While the inhibitory activity of P-0001 or P-0002 on any Raf kinase isimportant to their activity in treating disease, the compounds describedherein show favorable properties that provide advantages as apharmaceutical as well. In addition to demonstrating kinase inhibitoryactivity against Raf kinases in biochemical assays, compounds may showfavorable solubility, favorable pharmacokinetic properties, and low Cypinhibition. The compounds are assessed in the following assays orsimilar assays available to one skilled in the art.

Assays for biochemical and cell based activity are known in the art, forexample, as described in PCT publication WO 2007/002433, the disclosureof which is hereby incorporated by reference as it relates to suchassays. For example, the biochemical activity IC₅₀ values are determinedwith respect to inhibition of B-Raf kinase activity, c-Raf-1 kinaseactivity, or B-Raf V600E kinase activity, where inhibition ofphosphorylation of a peptide substrate is measured as a function ofcompound concentration. Compounds to be tested are diluted in dimethylsulfoxide to a concentration of 0.1 mM. These are serially diluted 15 μLinto 30 μL of dimethyl sulfoxide seven times in 96 well plates for atotal of 8 dilution points, and for each dilution point 1 μL is added toa well of an assay plate. Plates are prepared such that each well in a384 well plate contains 1 μL of compound in 10 μL volume with 0.1 ng Rafenzyme (i.e. any of B-Raf, c-Raf-1 or B-Raf V600E, Upstate Biotechnologyor prepared by methods known to one of skill in the art), 50 mM HEPES,pH 7.0, 50 mM NaCl, 2 mM MgCl₂, 1 mM MnCl₂, 0.01% Tween-20, 1 mM DTT,and 100 nM biotin-MEK1 as substrate. The reaction is started withaddition of 10 μL of 200 μM ATP (i.e. final 100 μM ATP). Afterincubation of the kinase reaction for 45 minutes at room temperature, 5μL/well of Stop Solution is added (25 mM Hepes pH 7.5, 100 mM EDTA,0.01% BSA with donor beads (Streptavidin coated beads, Perkin Elmer),acceptor beads (Protein A coated, Perkin Elmer), and anti phosphorMEK1/2 antibody (CellSignal), each at final concentration 10 μg/mL). Theplates are incubated for 3 hours at room temperature and read onEnvision reader (Perkin Elmer). Phosphorylation of Mek1 results inbinding of the anti-phosphor-MEK1/2 antibody and association of thedonor and acceptor beads such that signal correlates with kinaseactivity. The signal vs. compound concentration is used to determine theIC₅₀.

The inhibitory activity of P-0001 or P-0002 against Raf kinases as wellas other kinases in a biochemical assay shows selective activity to theRaf kinases. The data show IC₅₀ of <0.1 μM for B-Raf and c-Raf-1, and <1μM for B-Raf mutant V600E for both compounds, while for P-0001 activityfor Kit, TrkA and Src was between 1-10 μM, and Btk, Fms, Hgk, and Kdrwas greater than 10 μM and for P-0002 activity for Kdr and Src was ˜1μM, and Btk, Fms, and TrkA was greater than 10 μM.

As an indication of relative solubility, the turbidity of compounds inaqueous solutions is assessed. To assess possible compound properties indifferent physiological compartments, such as stomach, intestine, andblood, a series of aqueous buffers with varying pH is used. Thus eachcompound is diluted into four different physiologically relevant buffersand solution turbidity is measured by spectrophotometry. Theconcentration of compound that demonstrates turbidity by forming enoughinsoluble suspension to raise the average optical density above 0.01 atthree wavelengths (490, 535, and 650 nm) is used to define the limit ofthe compound solubility in that buffer.

Compounds are dissolved at a concentration of 25 mM in dimethylsulfoxide, then serially diluted 1:1 into a 96 well plate, diluting 10times in pure dimethyl sulfoxide, with the final well of each row adimethyl sulfoxide blank. In an assay plate, 99 μL of appropriate bufferis added to each well, and 1 μL of each sample dilution is added to thebuffer, achieving a range of final total concentrations in aqueoussolutions having different pH. The buffers used are Simulated GastricFluid (SGF-pH 1.5) 0.5M NaCl, pH 1.5; Simulated Intestinal fluid (SIF-pH4.5 and pH 6.8) 0.05M NaH₂PO₄, pH 4.5 and 6.8; and Hepes Buffer(HEPES-pH 7.4) 10 mM HEPES, 150 mM NaCl, pH 7.4. Control compoundspyrene, estriol and propranolol HCl are also assessed. Plates are spunand then mixed for 1 minute, and the absorbance is read using a TecanSafire II to read wavelengths in the visible range (490, 535, and 650nm) at four locations per well, reflecting the degree of turbiditypresent. The average optical density for each wavelength in each well isgraphed vs. compound concentration, and the concentration at which thecurve crosses a threshold O.D. of 0.01 for each wavelength is reportedas the endpoint turbidity assay result. The average of the threewavelengths is used to compare turbidity of compounds. Compounds areconsidered to have low solubility if the threshold concentration is<31.3 μM, moderate solubility if the threshold concentration is 31.3 μMto 250 μM, and high solubility if the threshold concentration is >250μM.

The following table provides data indicating the relative solubility(L=low, M=moderate, H=high) based on turbidity threshold concentrationat each pH for P-0001 and P-0002:

Compound turbidity threshold (L, M, H) number 1.4 4.5 6.8 7.4 P-0001 L LL M P-0002 L L M M

CYP (Cytochrome P450) enzymes are the major drug metabolizing enzymespresent in the liver. The inhibition of CYP enzyme activity (IC₅₀) foreach of CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4(BFC) and CYP3A4(BQ) isdetermined for compounds, where inhibition of metabolism of a knownsubstrate leads to a decrease in the fluorescence of the metabolizedproduct. The fluorescence of the product is monitored as a function ofcompound concentration.

Compounds are dissolved in dimethyl sulfoxide to a concentration of 100mM. These are diluted 1 μL into 82 μL of acetonitrile. An 11 μL aliquotof this solution is then added to 204 μL of cofactor mix (1.3% NADPHRegeneration system Solution A, 1.04% NADPH Regeneration system SolutionB from BD Biosciences, 5% acetonitrile and 0.05% dimethyl sulfoxide).These are then serially diluted 160 μL to 160 μL co-factor mix for atotal of 10 points. A 10 μL aliquot of this final mixture is dispensedinto 384 well assay plates and incubated for 10 minutes at 37° C. Enzymeand substrate mix (10 μL; 0.5 pmol CYP1A2/5 μM CEC; 1.0 pmol CYP2C9/75μM MFC; 0.5 pmol CYP2C19/25 μM CEC; 1.5 pmol CYP2D6/1.5 μM AMMC; 1.0pmol CYP3A4/50 μM BFC; or 1.0 pmol CYP3A4/40 μM BQ) is added to theseassay plates. Assay plates are incubated at 37° C. (CYP1A2-15 min;CYP2C9-45 min; CYP2C19, 2D6 and 3A4-30 min) and read in a Tecan Safire 2plate reader (CYP1A2, 2C19 and 3A4 409 ex/460 em; CYP2C9 and 2D6 409ex/530 em). The signal versus compound concentration is used todetermine the IC₅₀. The enzymes and substrates for this assay areobtained from BD Biosciences. While other factors are involved indetermining CYP effects in vivo, compounds preferably have IC₅₀ valuesof >5 μM, more preferably IC₅₀ values of >10 μM.

The following table provides data indicating the Cyp inhibitory activityfor P-0001 and P-0002:

Compound Cyp IC₅₀ (μM) number 1A2 2C19 2C9 2D6 3A4(BFC) 3A4(BQ)P-0001 >10 >10 >10 >10 >10 >10 P-0002 >10 >10 <5 >10 5-10 >10

Pharmacokinetic properties of compounds (including any solid forms orformulations thereof) are assessed in male Sprague Dawley rats or maleBeagle dogs. Rats are dosed daily with compound either by IV injectionsvia surgically implanted jugular catheters or by oral gavage (PO). Eachcompound is prepared as a 20 mg/mL stock solution in dimethyl sulfoxide,which is further diluted to provide the dosing stock at the desiredconcentration for the IV or PO formulations. For IV dosing, the dosingstock is diluted into a 1:1:8 mixture of Solutol®:ethanol:water. For POdosing, the dosing stock is diluted into 1% methylcellulose. In acassette format (or each compound, solid form thereof or formulationthereof is done individually), compounds are diluted to 0.5 mg/mL eachfor IV dosing and 0.4 mg/mL each for PO dosing and dosed at 1 mg/kg (2mL/kg) or 2 mg/kg (5 mL/kg), respectively. For IV dosed animals, tailvein blood samples are collected with lithium heparin anticoagulant at5, 15, 30, and 60 minutes and 4, 8, and 24 hours post dosing each day.For PO dosed animals, tail vein blood samples are collected with lithiumheparin anticoagulant at 30 minutes, 1, 2, 4, 8 and 24 hours post dosingeach day. Dogs are dosed daily by oral capsules in a suitableformulation at 50 mg/mL. Cephalic vein blood samples are collected withlithium heparin anticoagulant at 30 minutes, 1, 2, 4, 8 and 24 hourspost dosing each day. All samples are processed to plasma and frozen forlater analysis of each compound by LC/MS/MS. Plasma levels as a functionof time are plotted to assess the AUC (ng*hr/mL). Compounds according tothe present invention preferably show improved pharmacokineticproperties relative to previously described compounds, i.e. they havesubstantially higher values for one or more of AUC, Cmax and half-liferelative to previously described compounds.

All patents and other references cited in the specification areindicative of the level of skill of those skilled in the art to whichthe invention pertains, and are incorporated by reference in theirentireties, including any tables and figures, to the same extent as ifeach reference had been incorporated by reference in its entiretyindividually.

One skilled in the art would readily appreciate that the presentinvention is well adapted to obtain the ends and advantages mentioned,as well as those inherent therein. The methods, variances, andcompositions described herein as presently representative of preferredembodiments are exemplary and are not intended as limitations on thescope of the invention. Changes therein and other uses will occur tothose skilled in the art, which are encompassed within the spirit of theinvention, are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varyingsubstitutions and modifications may be made to the invention disclosedherein without departing from the scope and spirit of the invention.Thus, such additional embodiments are within the scope of the presentinvention and the following claims.

The invention illustratively described herein suitably may be practicedin the absence of any element or elements, limitation or limitationswhich is not specifically disclosed herein. Thus, for example, in eachinstance herein any of the terms “comprising”, “consisting essentiallyof” and “consisting of” may be replaced with either of the other twoterms. Thus, for an embodiment of the invention using one of the terms,the invention also includes another embodiment wherein one of theseterms is replaced with another of these terms. In each embodiment, theterms have their established meaning. Thus, for example, one embodimentmay encompass a method “comprising” a series of steps, anotherembodiment would encompass a method “consisting essentially of” the samesteps, and a third embodiment would encompass a method “consisting of”the same steps. The terms and expressions which have been employed areused as terms of description and not of limitation, and there is nointention that in the use of such terms and expressions of excluding anyequivalents of the features shown and described or portions thereof, butit is recognized that various modifications are possible within thescope of the invention claimed. Thus, it should be understood thatalthough the present invention has been specifically disclosed bypreferred embodiments and optional features, modification and variationof the concepts herein disclosed may be resorted to by those skilled inthe art, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the appended claims.

In addition, where features or aspects of the invention are described interms of Markush groups or other grouping of alternatives, those skilledin the art will recognize that the invention is also thereby describedin terms of any individual member or subgroup of members of the Markushgroup or other group.

Also, unless indicated to the contrary, where various numerical valuesare provided for embodiments, additional embodiments are described bytaking any 2 different values as the endpoints of a range. Such rangesare also within the scope of the described invention.

Thus, additional embodiments are within the scope of the invention andwithin the following claims.

What is claimed is:
 1. A compound selected from the group consisting ofN-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide,N-[3-(4-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamideand a pharmaceutically acceptable salt thereof.
 2. The compoundaccording to claim 1 that isN-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide,or a pharmaceutically acceptable salt thereof.
 3. The compound accordingto claim 1 that isN-[3-(4-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide,or a pharmaceutically acceptable salt thereof.
 4. A compositioncomprising the compound or salt thereof according to claim 1 and one ormore pharmaceutically acceptable excipients.
 5. A kit comprising thecompound or salt thereof according to claim
 1. 6. A kit comprising thecomposition according to claim 4.